Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells

Johnson, Joshua C.; Martinez, Osvaldo; Honko, Anna N.; Hensley, Lisa E.; Olinger, Gene G.; Basler, Christopher F.

doi:10.1016/j.antiviral.2014.04.014

Cited by 60 publications

(49 citation statements)

References 58 publications

(77 reference statements)

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“…We have previously summarized the numerous small molecules described in the literature as possessing antiviral activity that could be further evaluated for their potential EBOV activity alongside the few new antivirals. We have found that there is considerable prior knowledge regarding these small molecules possessing activity against EBOV in vitro or in animal models 5– 8 , and this includes a number of accessible FDA-approved drugs 2, 3, 9 . Another recent study has shown three approved ion channel blockers (amiodarone, dronedarone, and verapamil) inhibited EBOV cellular entry 9 .…”

Section: Introductionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.

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Section: Introductionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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“…Ebola virus disease is associated with an excessive inflammatory cytokine response; therefore, therapies that can control this host response may prove clinically beneficial. Recently, p38 MAPK inhibitors, particularly the standard compound SB202190, have been shown to inhibit Ebola virus-mediated cytokine production from human monocyte-derived dendritic cells in vitro (86). A series of pyridinyl imidazole inhibitors of p38 MAPK (e.g., SB202190 and p38inK III) inhibited viral entry into dendritic cells (86).…”

Section: Repurposing Existing Drugs For Treatment Of Ebola Patientsmentioning

confidence: 99%

“…Recently, p38 MAPK inhibitors, particularly the standard compound SB202190, have been shown to inhibit Ebola virus-mediated cytokine production from human monocyte-derived dendritic cells in vitro (86). A series of pyridinyl imidazole inhibitors of p38 MAPK (e.g., SB202190 and p38inK III) inhibited viral entry into dendritic cells (86). In line with the proinflammatory function of MAPK, dosing of the MAPK inhibitors resulted in much-reduced cytokine and chemokine release levels upon Ebola virus infection, an important feature to minimize Ebola virus virulence.…”

Section: Repurposing Existing Drugs For Treatment Of Ebola Patientsmentioning

confidence: 99%

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

Haque

Hober

Blondiaux³

2015

Antimicrob Agents Chemother

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c Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre-and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients.

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“…Several promising therapeutic candidates are currently being investigated, but none are FDA approved. Strategies such as treatment with antisense oligonucleotides, antibody-based therapies, and treatment with small molecules directed against specific viral as well as cellular factors have been tested, but the outcomes have been mixed (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Additionally, many of these therapies target only closely related strains of Ebola virus, making the development of treatments for other species of Ebola virus and Marburg virus a priority.…”

mentioning

confidence: 99%

Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors

Anantpadma

Kouznetsova

Wang

et al. 2016

Antimicrob Agents Chemother

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Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells

Cited by 60 publications

References 58 publications

Machine learning models identify molecules active against the Ebola virus in vitro

Machine learning models identify molecules active against the Ebola virus in vitro

Addressing Therapeutic Options for Ebola Virus Infection in Current and Future Outbreaks

Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors

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